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Viruses and cancer


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viruses that can lead to cancer

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Viruses and cancer

  1. 1. Viruses and Cancer Robert Miller MD
  2. 2. Viruses are responsible for 20% of malignant conditions in humans, including some of the most common cancers worldwide, and are especially common in immunosuppressed patients.The identification of viruses associated with cancersmay provide prognostic information or alternativetreatments. Moreover, vaccines are now available fortwo classes of viruses that are associated with cancer:hepatitis B virus and human papilloma viruses (HPV).With new molecular approaches for virus discovery,the number of cancers that can be linked to viruseswith certainty will grow in the next few years.
  3. 3. A virus is a small infectious agent that can replicate only inside theliving cells of an organism. Viruses can infect all types of organisms,from animals and plants to bacteria and archaea.About 5,000 viruses have been described in detail, although there aremillions of different types. Viruses are found in almostevery ecosystem on Earth and are the most abundant type ofbiological entity.Virus particles (known as virions) consist of two or three parts: i)the genetic material made from either DNA or RNA, ii) a protein coatthat protects these genes; and in some cases iii)an envelope of lipids that surrounds the protein coat when they areoutside a cell.
  4. 4. History of Virus• Viruses initially isolated in 1898 as miniscule infectious microbes that caused plant diseases• In 1909 Karl Landsteiner implicated a virus as the cause of polio• By the early 1920-’s the viruses that caused cowpox and herpes had been isolated and grown in culture• Jenner had shown that inoculation with cow pox prevent small pox
  5. 5. Mukherjee, Siddhartha(2010-11-16). The Emperor ofAll Maladies: A Biography ofCancer.
  6. 6. Hippocrates (c. 460 BC – c. Aelius Galenus or Claudius Galenus (AD370 BC) was 129–c. 200/c. 216), better known as Galenan ancient Greek physician of wasthe Age of Pericles (Classical prominent Roman (of Greek ethnicity) physicGreece), and is considered ian, surgeon and philosopher. Arguably theone of the most outstanding most accomplished of all medicalfigures in the history of researchers of antiquity
  7. 7. It was in the time of Hippocrates, around 400 BC, that a word for cancerfirst appeared in the medical literature: karkinos, from the Greek word for―crab.‖ The tumor, with its clutch of swollen blood vessels around it,reminded Hippocrates of a crab dug in the sand with its legs spread in acircle.Another Greek word would intersect with the history of cancer— onkos, aword used occasionally to describe tumors, from which the discipline ofoncology would take its modern name. Onkos was the Greek term for amass or a load, or more commonly a burden; cancer was imagined as aburden carried by the body.The Greeks had no microscopes. They had never imagined an entity calleda cell, let alone seen one, and the idea that karkinos was the uncontrolledgrowth of cells could not possibly have occurred to them. They were,however, preoccupied with fluid mechanics. The human body, Hippocratesproposed, was composed of four cardinal fluids called humors: blood, blackbile, yellow bile, and phlegm.The physician Claudius Galen, a prolific writer and influential Greek doctorwho practiced among the Romans around AD 160, brought Hippocrates’humoral theory to its apogee. For cancer, Galen reserved the mostmalevolent and disquieting of the four humors: black bile. Cancer, Galenictheory suggested, was the result of a systemic malignant state, an internal
  8. 8. History of Cancer Theories• Peyton Rous (a chicken virologist) in 1910 transmitted a chicken sarcoma from one chicken to another (even highly filtered substances) so must be a virus, RSV (Rous sarcoma virus)• In the 1920’s somatic mutation hypothesis theory of cancer (environmental toxins or radiation)• In 1935 Richard Schope reported a papilloma virus that cause tumors in rabbits• In the mid 1940’s discovered leukemia virus in mice and cats• In 1958 Denis Burkitt found an aggressive lymphoma in Africa that appeared to spread by infection (later found to be EBV or Epstein-Barr virus)• In 1959 Howard Temin showed that the RSV could alter the infected cells DNA and so it could write genetic information backwards a so called retrovirus
  9. 9. Howard TeminTemins description of how tumor viruses act on the genetic material of the cellthrough reverse transcription was revolutionary.This upset the widely held belief at the time of a popularized version of the"Central Dogma" of molecular biology posited by Crick who had claimed thatinformation flows exclusively from DNA to RNA to protein.Temin showed that certain tumor viruses carried the enzymatic ability toreverse the flow of information from RNA back to DNA using reversetranscriptase. This phenomenon was also independently and simultaneouslydiscovered by David Baltimore, with whom Temin shared the NobelPrize. Both scientists completed their initial work with RNA-dependent DNApolymerase with the Rous sarcoma virus.
  10. 10. Virus gets the DNA into the cell Uses the cell to make copies ofand it migrates into the nucleus it’s DNA in DNA replication
  11. 11. DNA makes RNA copies RNA goes out into the cell called transcription New viruses can break out of theRNA goes to ribosomes to make Cell in the lytic cycleproteins (new viruses) in translation
  12. 12. Retrovirus RNA Enzyme, reverse transcriptase
  13. 13. RNA and reverse transcriptase New DNA with high mutation rate
  14. 14. A retrovirus is an RNA virus that replicates in a host cell. First ituses its own reverse transcriptase enzyme to produce DNA fromits RNA genome, reverse of the usual pattern,thus retro (backwards). This new DNA is then incorporated into thehosts genome .The cell then treats the viral DNA as part of its own instructions,which it follows blindly, making the proteins required to assemblenew copies of the virus.A special variant of retroviruses are endogenousretroviruses which are integrated into the genome of the host andinherited across generations. When retroviruses have integratedtheir own genome into the germ line, their genome is passed on to afollowing generation. These endogenous retroviruses (ERVs),contrasted with exogenous ones, now make up 5-8% of the humangenome.Most insertions have no known function and are often referred to as"junk DNA". However, many endogenous retroviruses play importantroles in host biology. Because reverse transcription lacks the
  15. 15. The replication cycle of a retrovirus entails the insertion (integration) of aDNA copy of the viral genome into the nuclear genome of the host cell. Mostretroviruses infect somatic cells, but occasional infection of germline cells(cells that produce eggs and sperm) can also occur.Rarely, retroviral integration may occur in a germline cell that goes on todevelop into a viable organism. This organism will carry the inserted retroviralgenome as an integral part of its own genome - an endogenous retrovirus(ERV) that may be inherited by its offspring as a novel allele. Many ERVshave persisted in the genome of their hosts for millions of years. However,most of these have acquired inactivating mutations during host DNAreplication, and are no longer capable of producing virus.The majority of ERVs that occur in vertebrate genomes are ancient,inactivated by mutation, and have reached genetic fixation in their hostspecies. For these reasons, they are extremely unlikely to have negativeeffects on their hosts except under unusual circumstances.
  16. 16. 20% of Human DNA is retrovirus. Are we already part virus?Borg is a collective proper noun for a fictional alien race that appears asrecurring antagonists in various incarnations of Star Trek. The Borg are acollection of species that have been turned into cybernetic organismsfunctioning as drones of the Collective, or the hive.
  17. 17. Peyton Rous (1879 - 1970) As a pathologist he made his seminal observation, that a malignant tumor growing on a domestic chicken could be transferred to another fowl simply by exposing the healthy bird to a cell-free filtrate, in 1911.This finding, that cancer could be transmitted by a virus (now known as theRous sarcoma virus, or RSV, a retrovirus), was widely discredited by mostof the fields experts at that time.Since he was a relative newcomer, it was several years before anyone eventried to replicate his prescient results. Although clearly some influentialresearchers were impressed enough to nominate him to the NobelCommittee as early as 1926 (and in many subsequent years, until he finallyreceived the award, 40 years later—this may be a record for the timebetween a discovery and a Nobel Prize). In 1966 he was awarded a NobelPrize in Physiology or Medicine for his work.
  18. 18. RVSRSV possesses only four genes in its genome, finally pinpointedRSV’s cancer-causing ability to a single gene in the virus. Thegene was called src (pronounced ―sarc‖), a diminutive of sarcoma.It encoded a protein whose most prominent function was to modifyother proteins by attaching a small chemical, a phosphate group,to these proteins.These enzymes were called the ―kinases,‖ and they were soonfound to behave as molecular master switches within a cell.Bishop and Varmus found a nearly identical version of viral srclodged firmly in the normal cell’s genome. Viral src— the cancer-causing gene— was cellular src on overdrive. precursor of acancer-causing gene— the ―proto-oncogene,‖ as Bishop andVarmus called it— was a normal cellular gene.
  19. 19. Denis Parsons Burkitt 1911 - 1993During World War II, Burkitt served with the Royal Army Medical Corps inEngland and later in Kenya and Somaliland. After the war Burkitt decided hisfuture lay in medical service in the developing world and he moved toUganda. He eventually settled in Kampala and remained there until 1964.Burkitt made two major contributions to medical science related to hisexperience in Africa. The first was the description, distribution, andultimately, the etiology of a pediatric cancer that bears his name BurkittslymphomaHis second major contribution came when, on his return to Britain, Burkittcompared the pattern of diseases in African hospitals with Western diseases.He concluded that many Western diseases which were rare in Africa werethe result of diet and lifestyle. He wrote a book Dont Forget Fibre in yourDiet, which was an international best-seller.
  20. 20. Henry Kaplan 1918-1984Stanford MedicalLinearAccelerator in1955 and also inthe 1975 lab toresearch cancerviruses
  21. 21. Henry Kaplan He is credited with finding that leukemias and cancers of the lymph system in mice were caused by a latent virus activated when radiation or chemicals suppressed the function of the animals normal immune system in 1959
  22. 22. Cancer Theories• By the 1960,s cancer was considered infectious, the NCI has a large Special Virus Cancer Program and Rous got the 1966 Nobel Prize• 1970’s efforts to prove that retro viruses caused most cancers failed (a few years later HIV)• cancer-causing gene— the ―proto-oncogene,‖ as Bishop and Varmus called it— was a normal cellular gene. Mutations induced by chemicals or X-rays caused cancer not by ―inserting‖ foreign genes into cells, but by activating such endogenous proto- oncogenes.
  23. 23. Genetics and CancerCancer, in short, was not merely genetic in its origin; itwas genetic in its entirety. Abnormal genes governedall aspects of cancer’s behavior. Cascades of aberrantsignals, originating in mutant genes, fanned out withinthe cancer cell, promoting survival, accelerating growth,enabling mobility, recruiting blood vessels, enhancingnourishment, drawing oxygen— sustaining cancer’slife.These gene cascades, notably, were perversions ofsignaling pathways used by the body under normalcircumstances.Mukherjee, Siddhartha (2010-11-16). The Emperor ofAll Maladies: A Biography of Cancer (pp. 387-388).
  24. 24. OncovirusAn oncovirus is a virus that can cause cancer. This term originated fromstudies of acutely transforming retroviruses in the 1950–60s. It now refers toany virus with a DNA or RNA genome causing cancer and is synonymouswith "tumor virus" or "cancer virus". The vast majority of human and animalviruses do not cause cancer, probably because of long-standing coevolutionbetween the virus and its host.Worldwide, the WHO International Agency for Research on Cancerestimated that in 2002 17.8% of human cancers were caused by infection,with 11.9% being caused by one of seven different viruses. The importanceof this is that these cancers might be easily prevented through vaccination(e.g., papillomavirus vaccines), diagnosed with simple blood tests, andtreated with less-toxic antiviral compounds.A direct oncogenic viral mechanism involves either insertion of additionalviral oncogenic genes into the host cell or to enhance already existingoncogenic genes in the genome.Indirect viral oncogenicity involves chronic nonspecific inflammationoccurring over decades of infection, as is the case for HCV-induced livercancer.
  25. 25. Cancer Viruses: ClassesThere are two classes of cancer viruses: DNA and RNA viruses.Several viruses have been linked to certain types of cancer inhumans. These viruses have varying ways of reproduction andrepresent several different virus families.DNA VirusesThe Epstein-Barr virus has been linked to Burkitts lymphoma.The hepatitis B virus has been linked to liver cancer in people withchronic infections.Human papilloma viruses have been linked to cervical cancer.Human herpes virus-8 has been linked to the development of Kaposisarcoma.RNA VirusesHuman T lymphotrophic virus type 1 (HTLV-I), a retrovirus, has beenlinked to T-cell leukemia.The hepatitis C virus has been linked to liver cancer in people withchronic infections.
  26. 26. Human Cancer VirusesVirus % of Cancer Types CancerHepatitis (HBV and 4.9% HepatocellularHCV)Human T-lymphotropic .03% Adult T cell leukemia(HTLV)Human Papillomavirus 5.2% Cervix, Anus, Vulva,(HPV) Vagina, OropharynxKaposi sarcoma associated 0.9% Kaposi sarcoma,herpesvirus (HHV-8) multicentic Castleman, primary effusion lymphomaMerkel cell polyomavirus NA Merkel cellEpstein-Barr (EBV) NA Burkitt, nasopharynx
  27. 27. Hepatitis and HepatomaHCC can develop in patients with chronic Hepatitis B even in the absenceof cirrhosis. However, 70 to 90 percent of patients with HBV who developHCC will have cirrhosisHepatitis C accounts for at least one-third of the cases of HCC in the UnitedStates. An important clinical observation is that HCC in patients with HCVoccurs almost exclusively in patients with advanced stages of hepaticfibrosis or cirrhosis.Attempts to prevent HCC should focus on preventing infection with HBVand HCV, treating patients with viral hepatitis who are candidates fortreatment, and attempting to prevent the development of cirrhosis inpatients with liver disease.
  28. 28. HepatomaHCC is related to chronic DNA changes related to HepB infection
  29. 29. Currently available hepatitis B vaccines are extremely safe and have anefficacy of >90 percent and are effective against all HBV serotypes andgenotypes. Thus, HBV infection can potentially be eradicated through globalvaccination.Surveillance for hepatocellular carcinoma (HCC) is recommended for many
  30. 30. Age-standardized death ratesfrom Liver cancer by country (per 100,000 inhabitants)
  31. 31. Human Cancer VirusesVirus % of Cancer Cancer TypesHepatitis (HBV and HCV) 4.9% HepatocellularHuman T-lymphotropic .03% Adult T cell leukemia(HTLV)Human 5.2% Cervix, Anus,Papillomavirus (HPV) Vulva, Vagina, OropharynxKaposi sarcoma associated 0.9% Kaposi sarcoma,herpesvirus (HHV-8) multicentic Castleman, primary effusion lymphomaMerkel cell polyomavirus NA Merkel cellEpstein-Barr (EBV) NA Burkitt, nasopharynx
  32. 32. HPV Types
  33. 33. Most Common STD2003-2004 National Health and Nutrition Examination Survey(NHANES) indicate 24 percent of female adolescents aged 14 to 19years had laboratory evidence of at least one of the followingsexually transmitted diseases (STD):Human papillomavirus (HPV, 18 percent)Chlamydia trachomatis (4 percent)Trichomonas vaginalis (3 percent)Herpes simplex virus type 2 (HSV-2, 2 percent)Neisseria gonorrhoeaeAmong girls who reported ever having had sex, 40 percent hadlaboratory evidence of one of the four STD, predominantly HPV (30percent) and chlamydia (7 percent).
  34. 34. HPV InfectionsHuman papillomavirus (HPV) is the most commonly diagnosedsexually transmitted infection in the United States.The HPV genome encodes DNA sequences for six early (E) proteinsassociated with viral gene regulation and cell transformation.The two most important HPV proteins in the pathogenesis ofmalignant disease are E6 and E7. At the molecular level, the abilityof E6 and E7 proteins to transform cells relates in part to theirinteraction with two intracellular proteins, p53 and retinoblastoma(Rb),Following E6 binding of p53, is degraded in the presence of E6-associated protein. This allows unchecked cellular cycling, and hasan anti-apoptotic effect. The HPV E7 protein disrupts cell cyclingleading to an increase in cellular p16 protein expression
  35. 35. Human Papillomavirus (HPV) infection of epithelial cells.HPVs infect basal cells of squamous epithelia through sites of mechanical trauma.Infections with high-risk HPVs can lead to dysplasia and carcinoma in situ and toinvasive squamous cell carcinoma. Progression is a rare and slow process andmany lesions regress spontaneously.
  36. 36. HPV Cancers Cancers Percent Cervix > 99% Anus 84% Vagina 70% Penis 47% Vulva 44% Oropharynx 36% Oral Cavity 24% JCO May 2011;29:1785
  37. 37. HPV Cancers 2004-2008Cancer All Cases HPV CausedCervix 11,967 11,500Vulva 3,136 1,600Vagina 729 500Penis 1,046 400Anus (female) 2,900 2,700Anus (male) 1,678 1,600Oropharynx (female) 2,370 1,500Oropharynx (male) 9,356 5,900
  38. 38. It has been estimated that at least 50 percent of sexually activewomen (and men) are exposed to HPV once in their lifetime.However, many experts believe that virtually all sexually activeadults have been infected by HPV for the following reasons:Most HPV infections are transient, and can come and go betweenmeasures of HPVThere are more than 40 HPV types that infect the entire lowergenital tract, including the vaginaMost HPV infections, including carcinogenic HPV genotypes,typically resolve within 6 to 12 months. However, women withpersistent carcinogenic HPV infections are at risk of developingprecancerous lesions, although not all persistent infectionsprogress.In the United States, the median age of cytologically-detectedprecancerous lesions occurs approximately 10 years after themedian age of sexual debut
  39. 39. Explaining the rise in oropharyngeal HPVinfections since the 1980’s, changingsocial norms
  40. 40. HPV Oropharynx CancerEpidemiologic studies have demonstrated that there has been a decrease inthe incidence of laryngeal, hypopharyngeal, and oral cavity cancers,beginning in the late 1980s. This decline is believed to reflect the gradualdecrease in smoking, which is a primary risk factor for these cancers.Despite the decrease in tobacco use, the incidence of oropharyngeal cancerinitially remained constant and then began to rise due to HPV relatedcancers arising in the base of the tongue and the tonsillar region.Furthermore, this association is primarily with HPV-16 suggested thatapproximately 50 percent of oropharyngeal cancers were due to HPV, whilemore recent studies suggest that HPV may account for much as 70 to 80percent of these malignanciesThe overall prevalence of HPV DNA in oral exfoliated cells was 6.9 percent,and the prevalence of HPV16 was 1.0 percent. The prevalence of HPVinfection followed a bimodal distribution, with peaks at ages 30 to 34 and 60to 64 years (7.3 and 11.4 percent, respectively). HPV prevalence wasapproximately three-fold more common in men compared with women (10.1versus 3.6 percent), consistent with the observed sex distribution for HPVassociated oropharyngeal cancer.
  41. 41. New Cancer Cases in the US in 2013 Site Male Female Tongue 9,900 3,690 Mouth 6,730 4,670 Pharynx 11,200 2,730Oral (other) 1,790 670
  42. 42. Oropharynx (base of tongue ortonsil)
  43. 43. Human Papillomavirus and RisingOropharyngeal Cancer Incidence in the United States JCO November 10, 2011 vol. 29 no. 32 4294-4301
  44. 44. Percent of Men Reporting Type ofSexual Activity in the Past Year (2010) 100 Vaginal Intercourse 90 Fallatio 80 Cunnilingus 70 60 50 40 30 20 10 0 20 30 40 50 60 70 Man’s Age
  45. 45. Percent of Women Reporting Sexual Activity in the Past Year (2010) 100 Vaginal Intercourse 90 Fallatio 80 Cunnilingus 70 60 50 40 30 20 10 0 20 30 40 50 60 70 Woman’s Age
  46. 46. HPV in MenThe rate of genital HPV infection among males is similar to that infemales. In any 12-month period, the probability that a sexuallyactive male will acquire a new genital HPV infection is 0.29 to0.39, which is similar to estimates for females.However, there are differences between the sexes in the immuneresponse to HPV. A larger proportion of females are HPV-seropositive (17.9%, vs. 7.9% of males), and females have highertiters of antibodies. The lower immune response to natural infectionin males may partially explain the higher prevalence of HPVinfections as compared with the prevalence among females, and theconstant prevalence and incidence of HPV infection across a wideage range in males. prophylactic vaccination of boys and men with quadrivalent HPVvaccine may reduce the incidence of condylomata acuminata, asobserved within 3 years after the introduction of a vaccination N Engl J Med 2011; 364:401-411
  47. 47. Pathology – The vast majority of HPV associated head and neckcancers are squamous cell carcinomas. Immunohistochemistry(IHC) for p16 is highly sensitive for HPV associated tumorsEpidemiologic factors – Patients with HPV positive oropharyngealcancer are approximately 10 years younger when compared to HPVnegative patients. Many of the patients seen with this entity are intheir late thirties or early forties.Anatomic location – HPV associated tumors predominantly arise inthe base of the tongue or the tonsillar region,Stage: more likely to present with a relatively earlystage (T1/T2) primary tumor, but relatively advanced disease in theneck (N2/N3), often with a large cystic lymph node than issometimes mistaken for a cyst. Despite the biologic aggressivenessof HPV positive cancer, these tumors appear to have a betterprognosis than head and neck cancers not associated with HPV witha lower rate of distant metastases, significantly less likely to have asecond malignancy
  48. 48. Typical smoking relatedoropharynx cancer, presented withmonths of throat pain radiating intoear
  49. 49. HPV Oropharynx Cancer50 yo man, non-smoker presented with cystic neck nodes and occultprimary in the base of tongue
  50. 50. HPV Oropharynx Cancer 53 yo man with large cystic neck node and occult primary in base of tongue
  51. 51. HPV Tonsil Cancer 63 yo non-smoker man presents with neck mass and small lesion in tonsil He was non-smoker Bx = squamous ISH = high risk HPV IVA (T1N2b)
  52. 52. HPV Tonsil Cancer
  53. 53. Effect of HPV-Associated p16INK4AExpression on Responseto Radiotherapy in Squamous Cell Carcinoma of the Head and Neck Local Control JCO April 20, 2009 vol. 27 no. 12 1992-1998
  54. 54. Overall SurvivalJCO April 20, 2009 vol. 27 no. 12 1992-1998
  55. 55. The cure rate is better for HPV oropharynxcancers than for smoking related cancers SURVIVAL Non-smokers smokers Years JCO June 10, 2012 vol. 30 no. 17 2102-2111
  56. 56. Chemoradiation HPV + HPV - JCO September 20, 2010 vol. 28 no. 27 4142-4148
  57. 57. Quick Response to Radiationcombined with chemotherapy, Tonsilcancer gone by 2 ½ weeks
  58. 58. Chemoradiation for Tonsil Cancer
  59. 59. Cure Rates for Advanced Head andNeck Cancer with Chemo-Radiation Cisplatin Erbitux (cetuximab)Failure-free survival among patients with cancer of oropharynx, hypopharynx, or larynx; IJROBP 2011:81;915
  60. 60. RTOG 1016 Protocol InformationPhase III Trial of Radiotherapy Plus CetuximabVersus Chemoradiotherapy in HPV-AssociatedOropharynx Cancer Primary Objective:To determine whether substitution of cisplatin with cetuximab will result in comparable 5-year overall survival Patient Population:Squamous cell carcinoma of the oropharynx (tonsil, base of tongue, soft palate, or Oropharyngeal walls); stage T1-2, N2a-3, or T3-4 any N; patient tumor must be p16 positive
  61. 61. HPV related cancers now cause 60 to 70%of oropharynx cancers in the US (esp. HPV16) These patients have a superiorresponse to therapy and better outcome.Testing can be done for HPV by ISH or p16by IHC. Ongoing trials will determinewhether to use this information to modifytherapy
  62. 62. GardasilRecommend HPV immunization of females, as advised by multipleexpert panels . Routine immunization should be offered to girls 11to 12 years of age, but can be administered as early as nine years.Catch-up vaccination should be offered for females aged 13 to 26years who have not been previously vaccinated.Recommend the use of quadrivalent HPV vaccine in males, asadvised by expert panels. Routine immunization should be offeredto boys aged 11 to 12, but can be administered as early as nineyears of age. Catch-up vaccination should be offered for malesbetween the ages of 13 to 21 who have not been previouslyvaccinated. For MSM, catch-up vaccination should be offered up toage 26.
  63. 63. Human Cancer VirusesVirus % of Cancer Cancer TypesHepatitis (HBV and HCV) 4.9% HepatocellularHuman T-lymphotropic .03% Adult T cell leukemia(HTLV)Human Papillomavirus 5.2% Cervix, Anus, Vulva,(HPV) Vagina, OropharynxKaposi sarcoma 0.9% Kaposi sarcoma,associated herpesvirus multicentic(HHV-8) Castleman, primary effusion lymphomaMerkel cell polyomavirus NA Merkel cellEpstein-Barr (EBV) NA Burkitt, nasopharynx
  64. 64. Kaposi SarcomaKaposi sarcoma (KS)It was originally described by Moritz Kaposi an Hungarian dermatologistpracticing at the University of Vienna in 1872.It became more widely known as one of the AIDS-defining illnesses in the1980s. The viral cause for this cancer was discovered in 1994, it is atumor caused by Human herpesvirus 8 (HHV8), also known as Kaposisarcoma-associated herpesvirus (KSHV). Although KS is now well-established to be caused by a viral infection,there is widespread lack of awareness of this even among persons at riskfor KSHV/HHV-8 infection.
  65. 65. KS Lesions in AIDS Tom Hanks in the movie Philadelphia
  66. 66. Kaposi SarcomaKaposi sarcoma (KS) is a vascular tumor that is etiologically associated withhuman herpesvirus 8 (HHV-8), which is also known as the KS-associatedherpesvirus (KSHV). Although KS has been reported among all risk groupsfor HIV infection, it is most common in homosexual or bisexual men. AIDS-related KS is much less common in heterosexual injection drug users,transfusion recipients, women or children, and hemophiliacsIn patients with AIDS-related KS, the CD4 count appears to be the mostimportant factor associated with the development of KS.
  67. 67. HHV-8KS was rare until the early 1980s when, with the onset of the HIVepidemic, it was described in several homosexual men in NorthAmericaThe epidemiology of Kaposis sarcoma (KS) suggested a linkbetween the development of disease and a transmissible agent.In 1994, a novel gamma herpesvirus was subsequently identified inKS biopsies. HHV-8 fits most closely into the family of humangamma herpesviruses, which includes Epstein-Barr virus. Gammaherpesviruses play an important role in cellular proliferation and thedevelopment of malignanciesThe exact mode(s) of transmission for HHV-8 remains unclear.Saliva appears to be a source of infectious virus. It has beenproposed that saliva may be the main mode of HHV-8 transmissionin children and that it could be a source of mother-to-childtransmission. Other possible modes of transmission include sexualtransmission, blood transfusions, and solid organ transplantation
  68. 68. Neglected HIV with Advanced KS in the Mouth
  69. 69. Human Cancer VirusesVirus % of Cancer Cancer TypesHepatitis (HBV and HCV) 4.9% HepatocellularHuman T-lymphotropic .03% Adult T cell leukemia(HTLV)Human Papillomavirus 5.2% Cervix, Anus, Vulva,(HPV) Vagina, OropharynxKaposi sarcoma associated 0.9% Kaposi sarcoma,herpesvirus (HHV-8) multicentic Castleman, primary effusion lymphomaMerkel cell NA Merkel cellpolyomavirusEpstein-Barr (EBV) NA Burkitt, nasopharynx
  70. 70. Friedrich Sigmund Merkel(5 April 1845 – 28 May 1919) was a leading German anatomist a nd histopathologist o f the late 19th century.
  71. 71. Merkel Cellare oval receptor cells found in the skin that have synaptic contactswith somatosensory afferents. They are associated with the sense of lighttouch discrimination of shapes and textures. they contain dense coregranules, and thus may also have a neuroendocrine function. Merkel Cell
  72. 72. Merkel CellMerkel cell carcinoma (MCC) of the skin is a rare, aggressive cutaneousmalignancy that predominantly affects elderly Caucasians and has apropensity for local recurrence and regional lymph node metastases.Merkel cell polyomavirus is a non-enveloped, double-stranded DNA virusthat may be causally linked to the development of MCC. The observationthat the integration of the virus into the tumor genome precedes the clonalexpansion of tumor cells supports a pathogenic role for this virus.Reported prevalence rates for Merkel cell polyomavirus in tumors have foundthe virus in around 80 percent of MCCs may be present in all MCC tumors
  73. 73. Merkel cell carcinoma - polyomavirusMerkel cell carcinoma - immunohistochemical stain for Merkel cellpolyomavirus A CM2B4 immunohistochemical stain reveals strongimmunoreactivity of Merkel tumor cells for an antibody targeting the Merkelcell polyomavirus.
  74. 74. • Rare, aggressive tumor with local recurrence rate of 25-30% and distant metastases in 35%• 5 Year survival is 30 – 64%• More common in older white men, with high sun exposure and in immunosuppressed• The Merkel Cell Polyomavirus (MCV) identified in 2008 is found in 43 to 100% and its role in the pathogenesis is under investigation
  75. 75. Human Cancer VirusesVirus % of Cancer Cancer TypesHepatitis (HBV and HCV) 4.9% HepatocellularHuman T-lymphotropic .03% Adult T cell leukemia(HTLV)Human Papillomavirus 5.2% Cervix, Anus, Vulva,(HPV) Vagina, OropharynxKaposi sarcoma associated 0.9% Kaposi sarcoma,herpesvirus (HHV-8) multicentic Castleman, primary effusion lymphomaMerkel cell polyomavirus NA Merkel cellEpstein-Barr (EBV) NA Burkitt, nasopharynx
  76. 76. EBV Epstein-Barr virus (EBV) is a widely disseminated herpesvirus, which isspread by intimate contact between susceptible personsand asymptomatic EBV shedders. The majority of primaryEBV infections throughout the world are subclinical andunapparent. Antibodies to EBV have been demonstratedin all population groups with a worldwide distribution;approximately 90 to 95 percent of adults are EBV-seropositive.EBV is the primary agent of infectiousmononucleosis, persists asymptomatically for life in mostadults, and is associated with the development of B celllymphomas, T cell lymphomas, Hodgkin lymphoma andnasopharyngeal carcinomas in certain patients.
  77. 77. Burkitt LymphomaBurkitt lymphoma (BL), which is characteristically localized in the jaw, is themost common childhood malignancy in equatorial Africa. More than 95percent of African children are infected with EBV by age three, whereas, inaffluent countries, primary infection is often delayed until adolescenceMalaria and EBV infection are considered cofactors in the genesis ofBurkitt lymphoma.
  78. 78. Hodgkins and NasopharynxAmong HIV-infected patients, EBV infection has been associated with non-Hodgkin lymphoma and, in children, smooth muscle tumors. EBV genomic DNA was first reported in tissue specimens from patientswith Hodgkin lymphoma (HL) in 1987. The finding that the malignant cells inHL, including the characteristic Reed-Sternberg cells, contain the EBVgenome in up to 50 percent of "Western" cases supports a pathogenic rolefor EBV in this malignancy Nasopharyngeal carcinoma is relatively rare in most populations. However,it is one of the most common cancers in southern China. In contrast toBurkitt lymphoma, the association of EBV with nasopharyngeal carcinomais highly consistent in both low- and high-incidence areas and EBV ispresent in every anaplastic nasopharyngeal carcinoma cell
  79. 79. ChemoradiationNasopharynx
  80. 80. xenotropic murine leukemia virusXenotropic murine leukemia virus-related virus (XMRV) is agammaretrovirus that was first described in 2006. Initial reports linked thevirus to prostate cancer, and later to chronic fatigue syndrome (CFS), butthese were followed by a large number of studies in which no associationwas found. It has not been established that XMRV can infect humans, norhas it been demonstrated that XMRV is associated with or causes humandisease.
  81. 81. Cancer Information Cancer Videos Tomotherapy Cyberknife Other Topics Dr. Miller
  82. 82. www.aboutcancer.comCancer Information •Basic Cancer Information •General Cancer Statistics •Most Common Cancers * brain * breast * colon/rectum * gynecologic * lung * prostate •Other Specific Cancers Radiation or Chemotherapy •All Other Cancer Topics •Other Topics •Best Web Sites
  83. 83. Robert Miller MD Medical Channelbone metastasesbrain metastasesbreast cancer: understanding the disease, treatment decisionshead and neck cancer (mouth, throat, larynx understanding the disease, radiation treatmentlung cancer: understanding lung cancer, radiation treatmentsprostate cancer: understanding the disease, treatment decisions,radiation therapyskin canceruterine (endometrial cancer)